A Look at Voxelotor: HOPE Trial

EP: 1.Understanding Sickle Cell Disease

EP: 2.Prevalence and Burden of SCD

EP: 3.Acute and Chronic Complications in SCD 

EP: 4.Anemia-Related SCD Manifestation: Monitoring and Screening

EP: 5. Impact of SCD on Quality of Life

EP: 6.Hydroxyurea in Sickle Cell Disease

EP: 7.Role of L-Glutamine in SCD

EP: 8.Screening and Monitoring for Red Blood Cell Transfusion

EP: 9.Considerations for HSCT in Sickle Cell Disease

EP: 10.Benefits and Risks of HSCT in SCD

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EP: 11.A Look at Voxelotor: HOPE Trial

EP: 12.Voxelotor Use in the COVID-19 Pandemic

EP: 13.Use of Crizanlizumab for Pain Crisis Associated With SCD

EP: 14.Therapeutic Decision Making in SCD

EP: 15.Gene Therapy Approaches in SCD

EP: 16.Emerging Gene Therapy Methods in SCD

EP: 17.Stem Cell vs Gene Therapy Processes in SCD

EP: 18.Challenges in Global Access to SCD Treatments

EP: 19.What’s Next and Final Thoughts in SCD

Ifeyinwa Osunkwo, MD, MPH: We’re going to move to the next section, which is novel treatment options for sickle cell disease. In the past 2 years, we’ve had 2 drugs approved for sickle cell disease treatment. The first one is a drug called voxelotor, brand name is Oxbryta, and it’s a first-in-class hemoglobin S polymerization inhibitor. What they found in the study was it would increase your hemoglobin by at least 1 [g/dL] in more than half the patients, and at the same time reduce your markers of hemolysis. My question goes to Abdullah. What was the efficacy of voxelotor in both adults and young adults in the HOPE trial, over the 72 weeks of analysis?

Abdullah Kutlar, MD: The results from the first 24 weeks were published as a New England Journal of Medicine article last August, with Elliott] Vichinsky, [MD, being the lead author. It did show that people who were on 1500 mg a day had a better hemoglobin response, with a decrease in hemolysis. There was an abstract presented at ASH [the American Society of Hematology annual meeting] this past year that looked at the 72-week results of 1500 mg a day on voxelotor. It showed that almost 90%, 89% of the patients, who were on 1500 mg a day at the end of the 72 weeks had a 1 g/dL or greater increase in hemoglobin as opposed to only 25% on the placebo, which was significant at a P value of .001. Similarly, the decrease in hemolysis markers was clear. There was a 26% decrease in indirect bilirubin, 18% decrease in reticulocytes, and a 5% decrease in LVH [left ventricular hypertrophy]. When they looked at the number of VOCs [vaso-occlusive crises], numerically the VOCs were lower in the voxelotor group compared to placebo, but as of the time of that analysis this had not reached statistical significance. But the efficacy of voxelotor in increasing hemoglobin is well placed. The only issue is, again, adherence. We always have that component, and rightly so, because quite a few of our patients who were put on voxelotor come to me and say, “I’m not taking it. I had bad diarrhea” and all of that. And I have conveyed this to the manufacturers. I recently heard that they’re working on alternative formulations like powder forms. We need an improved formulation to make this more tolerable to our patients.

Ifeyinwa Osunkwo, MD, MPH: Wally, it also analyzed the hemoglobin vs pain episodes. Can you walk us through the data, both at 24 weeks and 72 weeks?

Wally Smith, MD: The background of this is important to explain to our listeners. Just like patients pay attention to hemoglobin, vaso-occlusion and crisis, and not much else, unfortunately so do doctors. If a drug doesn’t decrease your vaso-occlusive crises, then it’s no good. That’s been the knock on this drug and on any drug that does anything other than decrease the number of times patients come to the hospital. Now, I don’t criticize doctors for paying attention to vaso-occlusive crises; the number of crises one has per year on average is a predicator of mortality. I get it. If you decrease the number of vaso-occlusive crises, you’re likely to prolong life, and that’s the hydroxyurea story. But as you said, anemia is bad too. And you talked about that big meta-analysis that said the lower your hemoglobin, the shorter your lifespan, essentially. I propose to you, Ify, if you had a drug that did a little bit of both, if it decreased the number of crises, you had and it increased your hemoglobin, would that not be a nice compromise?

Ifeyinwa Osunkwo, MD, MPH: That would be good.

Wally Smith, MD: That’s what we have here. Now is it statistically significantly better? No. And that’s what this analysis said, that at 72 weeks the number of crises was not statistically significantly better. But the more response you had, and the better your hemoglobin response, the fewer crises you had, and they were able to show that very nicely. The incidence rate of vaso-occlusive crisis in this study was lowest in the patients who had the highest hemoglobin levels. And by the way, another knock on this drug was, “It’s going to kill people because it’s going to take their hemoglobin too high, and they’re going to die from strokes because of all that bad hemoglobin flowing around. It’s all going to clog up. It’s going to kill them.” And it seems to be doing the opposite so far. The best thing you could say is it’s safe. It’s safe for somebody to have a hemoglobin of 12 [g/dL] because their number of crises is actually going lower than if they had a hemoglobin of 10, or 11 [g/dL]. That was important to show, that this is a safe drug, you can safely get people’s hemoglobin levels higher. And rather than have more crises in that group of patients, you have fewer.

Abdullah Kutlar, MD: A couple of things here on Wally’s point, the hemoglobin response is important, obviously. But also, we must keep in mind that most people don’t have hemoglobin of 13, or 14 [g/dL], first of all. And secondly, in the case of voxelotor, having a high hemoglobin won’t be that bad, because the drug’s main effect is blocking the sickling, so that high hemoglobin will not polymerize as much in that case. That’s an important point.

Wally Smith, MD: I will agree with the skeptics who say the jury’s still out for whether this drug slows organ damage. But it’s also out for any other drug other than hydroxyurea.

Transcript Edited for Clarity